European Biotechnology News Special 7/2012 - Personalised Medicine

European Biotechnology News Science & Industry

July/August 2012

II Personalised Medicine

SPECIAL

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Special: perSoNaliSed MediciNe Intro

PM market growth and opportunities

© zentilia/Fotolia.com

Developing genetic tests that tell a pharma company whether to include volunteers in clinical trials or not is a significant emerging avenue of research, because they help increase the probability of proving efficacy. Patients that carry a targeted receptor can now be identified as responders, and health technology assessors can better determine for which patient group reimbursement makes sense. For doctors and regulatory authorities, the biomarker approach also suggests more accurate diagnoses, as well as better safety prediction. Many groups within the healthcare system could profit from the concept of “personalised medicine”. But before companies reap any benefits, researchers and diagnostics developers will first have to identify and validate biomarkers.

With data provided by the Human Genome Project, researchers can identify genetic biomarkers for responders and non-responders to personalised treatments.

The development of companion diagnostics tailored to targeted therapies has expanded rapidly since the 1998 market authorisation of Roche’s Herceptin, which works on patients overexpressing the Her2neu receptor. Initially, Herceptin proved a disappointment for Roche, because the antibody drug did not achieve its endpoints in a general population of breast cancer patients. However, after the pharma giant identified a relevant subgroup of responders carrying the Her2neu receptor, Herceptin grew into a “niche” buster with annual sales of US$6.4bn. The

model opened new vistas in drug development.Now the sector has begun looking for specific sub-groups that respond to specific substances. This year, the first “planned” personalised medicines – which come with companion diagnostics that have been developed along with the drug – hit the market: Pfizer’s lung cancer treatment Xalkori and Roche’s melanoma drug Zelboraf. Many others are in latestage testing. The pharmaceuticals industry is adapting its approach, and no longer thinks only in terms of the blockbuster model.

The development of personalised medicines is strongly dependent on finding valid biomarkers that can reliably identify responders and non-responders. This is the reason why biobanks have been revived across Europe and the world over in the last decade. They provide the necessary collections of patient tissue, blood, DNA and clinical data that allow researchers to screen for “omics” biomarkers in a relevant set of patients. With five million samples of its own, Europe’s largest biobank in Graz (Austria) is expected next year to become the headquarters of the BBMRI, a network of biobanks that links information on more than 200 million samples (see p. 36).

opportunity for diagnostics firms For diagnostics companies, progress in biomarker identification opens the gate to the emerging but high-risk market of companion diagnostics. According to experts from DiagnostikNet BB (see p. 38) collaboration with firms that focus on the development of personalised treatments in niche indications provides an opportunity to develop products even with a relatively low R&D budget.

Simulating disease based on patient characteristics is still in its infancy. However, so-called “systems medicine” approaches are in rapid development, and promise to provide expert systems to help verify difficult diagnoses (see p. 41).

The first milestones have already been achieved in one such project, where outcomes promise progress in predicting COPD in patients who are difficult to diagnose.

Market development of any biomarkerbased approach will be highly dependent on the acceptance of physicians – who tend to prefer conservative forms of treatment and diagnosis – and health technology assessors, who have to pay for the often very expensive treatments. Because every personalised treatment has the potential to both increase and decrease cost, it has to be evaluated individually.

As shown for cell therapies (see p. 42) it is not always cost-effective to personalise treatments.

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Nº 7-8 | Volume 11 | 2012

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SPECIAL: PERSONALISED MEDICINE BIOBANK GRAZ

A hub for competitive medical research Prof. Berthold Huppertz, Director and CEO, Biobank Graz, Medical University of Graz, Austria

Located at the Medical University of Graz in Austria, the Biobank Graz is the largest of its kind in Europe. It runs a quality management system, and allocates infrastructure and logistics to optimally support national and international research teams from both academia and industry. The Biobank Graz considers itself a research partner for fostering the development of monitoring and treatment in medicine on a personal level, thereby helping to introduce the public to personalised healthcare.

The Biobank Graz’s mission is to support research and development, especially in diagnosis, monitoring and treatment. Hence, the main goal of the publicly-owned entity is to contribute to advanced and sustained healthcare for the general population. The monitoring and treatment it provides are helping to introduce the public to the potential benefi ts of personalised medicine.

The quality management system in place at the Biobank Graz is run according to ISO 9001:2008. The overall aim of the facility is to help advance research through the collection, processing and

Fig. 1: Resources at the Biobank Graz

storage of human samples and their associated clinical data. As a non-profi t organisation, it gives special attention to sample and data quality, ethics and to the protection of patients’ individual rights.

Samples for personalised treatment strategies The Biobank Graz currently has more than fi ve million samples in storage that represent a non-selected patient group characteristic of central Europe. At Graz University Hospital, samples from selected patients and donors are deposited in the Biobank Graz only if these contributors have agreed and signed an informed consent form. Based on its collection strategy, the Biobank contains two groups of samples (Fig. 1): – A cross-sectional set of samples, including essentially unselected pathological samples and clinical data from the population of the Austrian state of Styria.

These samples, which have been collected and stored over the last 30 years, represent all of the diseases detected at the University Hospital at their “natural” frequency.

– A clinical set of samples with a focus on disease – including different types of human samples of the highest quality – and detailed clinical follow-up data from the entire course of the diseases in question.

This set of samples includes long-term observations for specifically selected diseases and targeted disease groups.

Together, these two sets of samples provide the ideal foundation for epidemiological studies, and allow researchers to validate biomarkers for the identification of specific diseases, as well as determine response to treatment. They can be used both for testing and the validation of strategies for personalised monitoring and treatment.

Supporting cutting-edge research that will have a global impact The Biobank Graz supports basic, translational and industrial research by providing data and samples to projects from national and international research teams (from both academia and industry) that have been ethically and scientifically approved. In this process, the Biobank itself plays the role of a research partner, and not simply that of a sample provider. The following are all available at a single hot-spot: 1 Well-established clinical experience at the University Hospital (clinical expertise) 2 Unique technology platforms at the Centre for Medical Research (technology advantages) 3 The largest biobank in Europe (service advantages).

The Biobank Graz plays an active, leading role in (inter)national projects and activities aimed at improving interactions between and cooperation amongst biobanks and scientists. It is a hub for national and international scientific networks, and can therefore help revolutionise securing human health by supporting strategies to implement personalised medicine. 

Contact: Prof. Berthold Huppertz, PhD berthold.huppertz@medunigraz.at

The implementation of individualized therapies requires diagnostic procedures based on modern technology and evaluation platforms which enable efficient, reliable analytics and evaluation of the biomarkers.

THE NETWORK‘S EXPERTISE

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Nº 7-8 | Volume 11 | 2012

Euro|Biotech|News

Special: perSoNaliSed MediciNe Personalised Medicine

Pharma and Dx firms share wider horizons Dr Frauke Adams, DiagnostikNet-BB, Hennigsdorf, Germany

Personalised medicine might be a popular catch-phrase at the moment, but the term often causes confusion, as there is still no uniform definition for it. The expression can include areas as diverse as the measurement of individual risk, early detection using biomarker testing, stratification of patients suffering from a disease and predictions about its course.

The term ‘companion diagnostics’ (CDx) is a much clearer expression. It refers to diagnostics linked to medications that enable predictions to be made about the effects (responder/non-responder) or dosage of a medication. Diagnostics therefore accompany any decisions made about therapy, and the two together are often described metaphorically as a tandem bicycle – with diagnostics steering in the front seat and therapy in the back pumping hard on the pedals. Companion diagnostics are used, for example, to stratify patients so that each subgroup receives the best therapy.

Tests are often developed at the same time as the medication (‘companion’) with the diagnostics forming part of the approval (label), although they can also be designed for existing therapies that are already on the market (as was the case for the HER2

test) or to verify success in clinical trials.

Personalised medicinal products benefit everyone involved: doctors can prescribe more effective and safer therapies for the patient, while the patient is spared unnecessary and stressful attempts to find the right therapy. For a pharmaceutical industry searching for the next blockbuster, stratification of patients may seem at first glance to act as a deterrent, as it decreases the size of the patient population under consideration. It has also grown increasingly difficult to verify a significant evidence-based additional benefit for new medicinal products. Nevertheless, the field of CDx offers many advantages to pharmaceuticals companies. For example, if there is a parallel diagnostic concept available that identifies responders/nonresponders or that excludes groups who

Pool Pool of suitableofpartners suitable partners

would suffer unjustifiable side effects, companion diagnostics increase market opportunities for a medication. Additionally, regulatory authorities have made it clear that in future, companies are expected to have a concept that enables the identification of responders and the exclusion of people with an unacceptable risk of side effects. And greater efficacy with lower risk for patients not only increases therapy compliance. It also creates a barrier for alternative therapy options not based on biomarkers. Diagnostic tests can increase the effectiveness of clinical studies and improve chances of receiving approval by providing evidence that the group of patients in question have benefited significantly. Efficiency also increases with faster recruitment of suitable volunteers.

Ideally, a diagnostic tool should be established as early as the development phase of a medicinal product. However, even after a product is available on the market, the combination of medicinal product and diagnostic tool expands the range of applications for the medication, and thus extends product life-cycle. By excluding non-responders, study results are also improved, meaning that even substances that have previously failed and are sitting in a pharmaceutical company’s basement (‘fallen angels’) can be dusted off and given a second chance.

cdx for biologicals For some companion diagnostics that are now established in the area of biologicals, approval for the medicinal product indicates a specific patient subgroup that must be confirmed diagnostically (e.g. Er-

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Nº 7-8 | Volume 11 | 2012

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Special: perSoNaliSed MediciNe

bitux and Vectibix are only for K-RAS wildtype patients). Current examples of parallel medication and companion diagnostic approvals include Zelboraf® (vemurafenib) from Roche – a treatment for an aggressive form of skin cancer – and Xalkori® (crizotinib) from Pfizer to treat non small-cell lung cancer. In the US, Zelboraf may only be used if the Cobas 4800 BRAF V600 test, which was developed by Roche and also approved by the FDA, is positive. The test detects a BRAF mutation that is present in about 50% of melanoma patients. Roche began developing the test kits in Phase I of the trials. Xalkori® is only effective in the 3–5% of patients in whom the anaplastic lymphoma kinase gene (ALK gene) is active, which inhibits the corresponding kinase. The test (Vysis ALK Break Apart FISH Probe Kit), which was developed by Abbott and submitted for approval at the same time, enabled Pfizer to obtain FDA approval within about three months, in part because the test precisely identified those patients who would probably benefit from the medication, and that in turn helped the company achieve good study results. With a ‘one drug fits all’ approach, Pfizer would have had no chance of succeeding in clinical trials with Xalkori for this numerically small group of patients with lung cancer.

Like the entire field of pharmaceutical development, personalised medicine is of course a high-risk area. Pharmaceutical companies are therefore not yet considering it as an alternative strategy, but rather as one that can complement the block-

buster strategy. Some businesses, however, have already started moving towards personalised medicine in order to capture at least a small market for particular active ingredients.

opportunity for diagnostics firms This cooperation also opens up attractive future opportunities for mediumsized niche providers. They can position themselves successfully with innovations that lead to the further development of known active ingredients, by for example improving efficacy and reducing side effects. In this case, CDx provides an opportunity – even with a relatively low R&D budget – to stabilise and secure products in development or even those already on the market in the area of the particular indication. Another impediment is that in many cases, doctors prefer conservative forms of treatment.

Experts assume, however, that more efficient and safer therapeutic agents are more quickly and widely used in clinical practice (increased adoption rate) while also boosting compliance, and thus the connection between the patient and the particular treatment strategy. Both regulatory requirements and the ability to reimburse diagnostics are the subject of current discussions in the area of personalised medicine.

The development of companion diagnostics for personalised medicine is a strategically important focus of the BB

diagnostics network (Netzwerk Diagnostik Berlin-Brandenburg e.V.). The network combines the expertise and resources of its 33 members. These companies include highly innovative medium-sized diagnostics companies, device manufacturers, suppliers, renowned research facilities and users from hospitals and medical laboratories in the Berlin-Brandenburg region, and they develop and produce in vitro diagnostic products along the entire valueadded chain. A Companion Diagnostics Working Group has been established within the network to initiate projects with pharmaceutical companies, because the CD concept requires close collaboration between experts who until now have worked separately in either the pharmaceutical or diagnostic business. The foundations for the practical implementation of personalised medicine are suitable technology platforms, such as testing and analytical procedures that enable biomarkers to be reliably identified, but which can also be used routinely in clinical practice.

The network provides diagnostic solutions for all phases of medicinal product development and the accompanying application.

The expertise available includes validation and evaluation of biomarkers (e.g. epigenetic and genetic markers, proteins, cellbased markers), clinical trials as well as the development, manufacture and marketing of test systems, devices, software and bioinformatics solutions.

For customers, the advantages of the BB diagnostics network is that joint development projects can be advanced quickly, and are driven by results for the benefit of the requesting pharmaceutical companies.

A network cooperative also minimises the risk of project failure, which can kill small diagnostics companies during the development and approval period or cause them to become financially dependent during the development process. Interested customers are more than welcome to contact the network management regarding any query or concern.

D

contact: Dr Frauke Adams f.adams@diagnostiknet-bb.de

Nº 7-8 | Volume 11 | 2012

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SIMULATION

Synergy COPD project reaches first major milestone

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The Technopol/Biotec Area Krems may be worth taking a look!

 Brussels/Munich – Deciding what treatment is most appropriate for patients with serious illnesses such as chronic obstructive lung disease (COPD) can present doctors with great difficulties. Even if potential benefits have been described in detail, complex treatments can often have both predictable and unpredictable side effects. Any given choice therefore is always accompanied by certain risks. Information and Communication Technologies (ICT) can provide doctors with tools to model and predict the (side-)effects of different treatment options in individual patients. Within the Synergy-COPD project (www.synergy-copd. eu) they link data from epidemiology, clinical trials and patient interviews to improve prediction of individual disease evolution and provide physicans with a decision support system.

The Technopol program of the federal state of Lower Austria strives to promote the development of business in certain technological fields by supporting Research, Education and Industry at specific sites of excellence in Lower Austria. Krems/Donau is our location for Medical Biotechnology where together with our partner organisation, Biotec Area Krems, we are investing in the following technological areas: Blood purification systems Tissue engineering Cell therapy Cell biology and cellular physiology Regenerative Medicine

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In silico personalised prediction of disease progression One year after the a4.5m EU project kicked off, researchers from For further information please contact g.hawa@ecoplus.at or office@biotec-area-krems.at project partner Biomax AG (Planegg, Germany) announced they have reached a first milestone. At PerMediCon in Cologne (19-20 June) Biomax Project Manager Dr. Dieter Maier announced that the consortium has established a comprehensive COPD knowledge base with a graphical front end for visualisations using Biomax’s BioXM technology. According to the bioinformatics specialist, the system integrates five well-established simulations of human physiology with biomedical data drawn from experimental studies, epidemiological data, clinical trials, physician interviews, a multi-center longitudinal study on COPD The third edition of the well-established „European Biotechnology phenotyping, and public datasets. The simulations, which link Industry Guide“ is now available. The brandnew book contains data genetic, clinical and metabolic data of the central and periphand information based on OECD criteria for more than 2,600 biotech eral O2 transport and utilisation, pulmonary gas exchange, recompanies active in the European Union, Switzerland and Norway on about 500 pages. gional-lung heterogeneities in ventilation and perfusion, skeletal muscle bioenergetics, and mitochondrial reactive oxygen e3 Volum species (ROS) generation, will lay the foundation for a decision support system that allows doctors to anticipate disease proes: gression and optimise therapy.

Featur Guide dustry ch In Biote Besides establishing a knowledge base, the Synergy-COPD an pe ro The Eu partners are aiming to create a so-called ‘inference engine’, and a ‘graphical visualisation environment’. The project ,which is coordinated by Barcelona Digital Centre Tecnològic (BDIGITAL), brings European Biotechnology together know-how in systems medicine from Germany‘s Biomax Industry Guide Vol. 3 Informatics AG (BIOMAX), Spain’s Linkcare Health Services S.L. E 98,00, ISBN 978-3-928383-38-7 (LINKCARE) and Consorci Institut d’investigacions Biomèdiques Tel. +49 (0)30/26 49 21-40 try Indus Fax +49 (0)30/26 49 21-11 August Pi i Sunyer (IDIBAPS), Sweden’s Karolinska Institutet (KI), service@biocom.de the UK’s Infermed Limited (INF) and Universities of Oxford and www.biocom.de y pean Euro chnolog Birmingham, as well as Hungary’s BME Budapest. Synergy COPD Biote is part of the European Commission’s Virtual Human Physiology programme, which supports about a dozen bio-IT projects. 

BOOK

European Biotechnology Industry Guide Vol. 3

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Nº 7-8 | Volume 11 | 2012

Euro|Biotech|News

SPECIAL: PERSONALISED MEDICINE STEM CELL THERAPY

Using progenitor cells to repair the liver Eric Halioua, CEO Promethera Biosciences, Mont-Saint-Guibert, Belgium

Because the liver is the site of many vital functions, impairment of a single protein within a complex metabolic pathway is usually highly detrimental. Such a condition is called an ‘inborn error’ of metabolism, and describes many genetic diseases linked to a nonfunctional enzyme in the liver. All these diseases affect the quality of life of patients and their families, and most have high mortality rates. Current treatments and long-term management are still not efficient enough, and patients would greatly benefit from a therapy that can meet this medical need. Orthotopic liver transplantation is the only curative treatment for severe defects and/or end-stage diseases, but that has major drawbacks: donor livers are rare, and the surgery is invasive and irreversible. Moreover, transplantation is not always an option, especially in newborns. Now cell therapy has been identified as the best potential tool for overcoming scarcity of organ donation.

Fig. 1: Promethera’s workflow for HepaStem development and use

The first cell therapy tested was liver cell transplantation, which consists of infusing allogenic mature hepatocytes isolated from healthy adult donors into the patient’s liver circulation (the vein leading to the liver).

The procedure has been well described, and around 30 clinical attempts have been reported in the literature. These proof-ofconcept studies established that it is feasible to bring missing function to a diseased liver with this method. However, several limitations in the use of mature hepatocytes prevent its wide application. Cells extracted from one liver can only be used to treat a single patient, and so the shortage of organs remains a problem. Moreover, hepatocytes lose their biological functionality when they are cryopreserved. And although hepatocyte transplantations can help stabilise severe inborn errors of metabolism, they do not cure them, and their effects are limited over time.

Dr. Etienne Sokal’s team at the Cliniques Universitaires Saint-Luc in Brussels discovered a progenitor cell in 2005 with properties that could potentially overcome these

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SPECIAL: PERSONALISED MEDICINE drawbacks. Called a HHALPC (Heterologous Human Adult Liver Progenitor Cell), this type of cell is a so-called “progenitor” adult cell, i.e. already predetermined to become a liver cell. Unlike hepatocytes, however, these cells are not yet mature, and therefore have greater potential for multiplication – they could make it possible to treat as many as a hundred patients from a single organ. The cells also live longer, and can be more easily multiplied and cryopreserved over long periods (Fig.1). Promethera Biosciences was set up in 2009 to exploit the potential of HHALPC for treating children suffering from serious congenital metabolic diseases.

Called HepaStem, this therapy has already received orphan drug designation (ODD) for the treatment of two very debilitating pediatric pathologies in Europe and the US: Crigler-Najjar syndrome and Urea Cycle Diseases. Promethera is now working on developing HepaStem for four congenital metabolic diseases as well as for the

acquired disease liver fibrosis. In 2012, the British (MHRA) and Belgian (AFMPS) regulatory authorities granted approval to initiate a Phase I/II pediatric clinical study in the two indications where ODD status has been given. This clinical trial is the very first to apply allogeneic liver progenitor cells.

Three patients have already been treated with the method at the Cliniques Universitaires Saint-Luc.

The study represents a major step in the development of liver progenitor cells as a therapy that could positively transform the prognosis for these very debilitating rare diseases. 

Contact: Eric Halioua, MBA Eric.Halioua@promethera.com

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